Chapter 13

1. Chapter 13 The Breast and Female Reproductive System

2. Learning Objectives • Describe normal structure and physiology of breast and common developmental abnormalities • Explain applications and limitations of mammography in the diagnosis and treatment of breast disease • Describe three common breast diseases that present as lump in the breast • Describe clinical manifestations of breast carcinoma, methods of diagnosis and treatment • Explain role of heredity in the pathogenesis of breast carcinoma

3. Learning Objectives • Describe common genital tract infections and relate these to sexually transmitted diseases • Describe clinical manifestations and complications of endometriosis • List common causes of irregular uterine bleeding • Describe common diseases of the cervix, endometrium, myometrium, and vulva

4. Learning Objectives • List common cysts and tumors of the ovary • Explain pathogenesis, clinical manifestations, treatment of toxic shock syndrome • Explain methods of artificial contraception and side effects; abnormalities in the genital tract following use of DES in pregnancy

5. Breast Structure (1 of 4) • Breasts: modified sweat glands specialized to secrete milk • Main function is milk production • Two main types of tissues • Glandular tissues (lobules and ducts) • Stromal (supporting) tissues • Supporting tissue includes fatty and fibrous connective tissue that give the breast its size, shape, and support • Two main types of breast changes • Benign (non-cancerous) • Malignant (cancerous)

6. Breast Structure (2 of 4) • Composed of 20 lobes of glandular tissue • Each lobe made up of a cluster of milk-producing glands or lobules • Lobules connected by branching ducts or small tubes and converge to the nipple • Fat and connective tissue, blood vessels, lymph vessels • Suspensory ligaments: bands of fibrous tissue extending from skin of breast to the connective tissue covering chest wall muscles

7. Breast Structure (3 of 4) • Abundant blood supply and lymphatic drainage • Lymph vessels carry lymph fluid instead of blood • Most lymph vessels of breast lead to the axillary nodes (supraclavicular and mediastinal nodes) • If breast cancer cells reach axillary nodes and continue to grow, nodes swell and cancer more likely to spread to other organs

8. Breast Structure (4 of 4) • Puberty: enlarge in response to estrogen and progesterone • Post-pubertal changes • Proliferation of glandular and fibrous tissue • Accumulation of adipose tissue • Variations in breast size depend on amount of fat and fibrous tissue rather than glandular tissue • Extremely responsive to hormonal stimulation • Menstrual cycle: cyclic hyperplasia followed by involution • Pregnancy and lactation: hypertrophic glandular and ductal tissues • After menopause: sex hormone levels decline, breasts gradually decrease in size

9. Tissue Changes Secondary to Hormone Levels Normal, non-pregnant Glandular hyperplasia, pregnant Postmenopausal atrophy

10. Breast Examination • Mammogram may identify lesions not detected on clinical examination • Denser cysts and tumors: white on mammogram • Less dense fatty tissue: dark on mammogram • Cysts and benign tumors: well circumscribed • Malignant tumors • Have irregular borders • Frequently contain fine flecks of calcium

11. Mammogram Cysts and tumors - white Fatty tissue: appear dark Fibrous and glandular tissue: appear as white strands

12. Calcifications Ductal carcinoma, with necrosis and calcification Stippled calcification in tumor

13. Abnormalities in Breast Development (1 of 3) • Embryologically, breasts develop from column of cells (mammary ridges) located anteriorly from axilla to upper thighs • Most of the ridges disappear during prenatal development except for those at the midthoracic area, giving rise to breasts and nipples

14. Abnormalities in Breast Development (2 of 3) • Accessory breasts and nipples: most commonly found in the armpits or on lower chest below and medial to the normal breasts • Unequal development: fully developed breasts are usually similar in size but not identical, sometimes one fails to develop as much as its counterpart

15. Abnormalities in Breast Development (3 of 3) • Breast hypertrophy: at puberty, one or both breasts over-respond to hormonal stimulation; true hypertrophy is from overgrowth of fibrous tissue, not glands or fat • Gynecomastia: ductal and fibrous tissue of adolescent male breast proliferate affecting one or more breast; from temporary imbalance of female and male hormones (increase in estrogen) in the male at puberty

16. Extra nipple below and medial to left breast and nipple Common sites of accessory breasts

17. Benign Cystic Change in the Breast • Very common benign condition; also called fibrocystic disease • Focal areas of proliferation of glandular and fibrous tissue • Irregular cyclic response to hormones during menstrual cycle • Ultrasound examination helpful in distinguishing a cystic from a solid mass • Treatment • Aspiration of cyst • Surgical excision if no aspiration

18. Benign breast cysts,in cross-section, previously filled with fluid Ultrasound, breast cyst

19. Fibroadenoma • Benign • Well-circumscribed tumor of fibrous and glandular tissue • Common in young women • Surgically excised

20. Breast Carcinoma • Risk factors • Familial tendency (mother or sister with breast cancer) • Hormonal factors • Birth of first child after age 30 • Early menarche • Late menopause • Occurs in both sexes, but rare in men, whose breasts are not subject to stimulation by ovarian hormones • Occurs in 1 in every 10 women

21. Breast Carcinoma • Hormones have been used for many years to treat menopausal symptoms consisting of estrogen alone or estrogen + progestin • Progestin: synthetic compound with progesterone activity • Combined hormone therapy (estrogen-progestin) increases density of breast tissue, complicating the interpretation of mammograms • Risk related to hormone treatment • Long-term estrogen-progestin use significantly increases risk of breast carcinoma (8%) • Long-term use of estrogen without progestin slightly increases risk of breast carcinoma (1%)

22. Breast Carcinoma • Inheritance of mutant breast cancer susceptibility genes • Mutant BRCA1 gene • Increases breast and ovarian carcinoma risk • Breast cancer risk at 80% • Ovarian cancer risk at 20–40% • Large gene with many different mutations • Mutant BRCA2 gene • Breast cancer risk at 80% • Lower ovarian carcinoma risk at 10–20% -still higher than average

23. Breast Carcinoma (4 of 4) • Clinical Manifestations • Lump in the breast • Nipple or skin retraction • Skin edema (orange peel sign) • Tumor infiltrates breast and becomes fixed to chest wall; metastasis

24. Classification of Breast Carcinoma • Site of origin • Ductal carcinoma (90%) • Lobular carcinomas (10%) • Non-infiltrating or in situ cancer • Confined initially within the duct or lobule • Becomes invasive and extends toward adjacent breast tissue • Presence or absence of invasion • Degree of differentiation of tumor cells • Well-differentiated: cells that resemble normal breast tissue • Poorly-differentiated: bizarre cells arranged haphazardly; immature; very different from normal breast tissue

25. Evolution of Breast Carcinoma • Early stages: too small to be detected by breast exam • Mammogram can identify carcinoma up to 2 years before detection by breast exam • Cancer continues to grow, initially in situ; eventually becomes invasive • Metastasizes to axillary lymph nodes and distant sites • Problems with late metastases • Early diagnosis allows prompt treatment and improves the cure rate

26. Breast Cancer

27. Breast Carcinoma Treatment: Surgical Resection • Modified radical mastectomy • Also called total mastectomy with axillary lymph node dissection • Resecting entire breast, axillary tissue with lymph nodes; leaves pectoral muscles • May be followed by breast reconstruction • Partial mastectomy: removing only part of breast with the tumor • Lumpectomy: removing tumor and small amount of adjacent breast tissue • Axillary lymph nodes removed in both lumpectomy and partial mastectomy followed by radiation to eradicate any remaining carcinoma in the breast

28. Breast Carcinoma Treatment: Adjuvant Therapy • To eradicate any tumor cells that may have spread beyond the breast • Anticancer drugs (adjuvant chemotherapy) • Anti-estrogen drugs (adjuvant hormonal therapy) • Whichever method of treatment is selected, part of tumor obtained is surgically tested to: • Detect presence of estrogen and progesterone receptors • Detect amplification of HER-2 gene that speeds growth rate of tumor cells; HER-2 positive tumors have less favorable prognosis

29. Determining Hormone Receptor Status of Tumor • Prognosis • Estrogen receptors (ER) and progesterone receptors (PR) in breast carcinoma • Hormone receptor positive tumors are better differentiated with favorable prognosis • Patients with ER positive tumors may receive adjuvant hormonal therapy with antiestrogen drug • Guide for treatment: tumors with hormone receptors respond to anti-estrogen adjuvant therapy

30. Recurrent and Metastatic Carcinoma (1 of 2) • May appear many years after original tumor has been resected • Tumor no longer curable, treatment is to control growth, relieve symptoms, and improve quality of life • Methods of treatment depend on the following factors: • Hormone receptor status of tumor • Age of patient • Length that elapsed from initial treatment to appearance of metastasis • Pre- and postmenopausal, hormone-receptor positive tumor: use anti-estrogen drugs

31. Recurrent and Metastatic Carcinoma (2 of 2) • Methods of treatment • Hormone-receptor positive tumor • Premenopausal: anti-estrogen drugs • Postmenopausal: aromatase inhibitor drugs • Hormone-receptor negative tumor • Hormonal manipulation if unresponsive to tamoxifen or aromatase inhibitor • Radiation • To control metastatic deposits in bone and soft tissues

32. A Lump in the Breast • Diagnostic possibilities • Cystic disease • Fibroadenoma • Carcinoma • Diagnostic approach • Clinical evaluation • Mammogram • Biopsy

33. Discussion • Which statement regarding breast cancer risk is UNTRUE? A. Late menses and early menopause can increase breast cancer risk B. Risk is higher in families with a history of breast cancer C. Hormone use can increase the risk of breast cancer D. The risk is higher for women who have never borne children

34. Female Genital Tract: Infections (1 of 3) • Vaginitis: common, causes vaginal discharge, itching, and irritation • Candida albicans • Trichomonas vaginalis • Gardnerella (Hemophilus) vaginalis in conjunction with anaerobic bacteria (nonspecific vaginitis) • Cervicitis: mild chronic inflammation; common in women who have had children • More severe inflammation caused by gonococci or Chlamydia • May spread to infect tubes and adjacent tissues (PID)

35. Female Genital Tract: Infections (2 of 3) • Salpingitis: tubal infection • Pelvic inflammatory disease, PID: inflammation of fallopian tubes, along with ovaries at times • Manifestations and complications • Lower abdominal pain and tenderness, fever, leukocytosis • Usually secondary to ascending spread of cervical gonorrheal or Chlamydial infection • Tubal scarring following healing predisposes to ectopic pregnancy or may cause sterility

36. Female Genital Tract: Infections (3 of 3) • Condylomas: venereal warts in genital tract • Benign tumor-like overgrowths of squamous epithelium • Acquired and transmitted by sexual contact • Common locations • Mucosa of cervix and vagina • Around vaginal opening • Around anus • Treatment: to destroy lesions • Applying a strong chemical • Electrocoagulation • Freezing • Surgical excision

37. Chronic pelvic inflammatory disease, swollen tubes with occluded fimbriated ends Multiple condylomas in cervical and vaginal mucosa

38. Endometriosis (1 of 2) • Deposits of endometrial tissue outside normal location in endometrial cavity • Ectopic sites: uterine wall; ovary; elsewhere in pelvis, appendix; rectum • Ectopic endometrium responds to hormonal stimuli and undergoes cyclic menstrual desquamation and regeneration • Secondary scarring may obstruct fallopian tubes • Diagnosis: laparascopy • Allows visualization of ectopic deposits followed by removing or destroying these deposits surgically, through drugs, or hormones

39. Endometriosis (2 of 2) • Treatment • Synthetic hormones with progesterone activity to completely suppress menstrual cycle • Oral contraceptives to suppress ovulation: makes endometrium thin and atrophic and menstrual cycles light, which retards progressing of endometriosis and associated scarring • Drugs that suppress output of gonadotropin from pituitary gland: leads to decline in ovarian function, allowing deposits of endometriosis to regress by being deprived of cyclic estrogen-progesterone stimulation

40. Endometriosis, cystic deposit of endometriosis filled with old blood in uterine wall

41. Cervical Polyps • Cervical polyps • Benign, arise from the cervix • Usually small but may be quite large • Erosion of tip may cause bleeding • Surgical removal • Cervical dysplasia: abnormal growth and maturation of cervical squamous epithelium • Dysplastic changes range from: • Mild dysplasia • Result of cervical inflammation • Regresses spontaneously • Severe dysplasia • Does not regress • May progress to in situ carcinoma • May progress to invasive carcinoma

42. Large cervical polyp

43. Cervical Intraepithelial Neoplasia (1 of 2) • Cervical dysplasia and in situ carcinoma considered very closely related • Constitute different stages in a progressive spectrum of epithelial abnormalities classified as cervical intra-epithelial neoplasia, CIN • Grade I: Mild dysplasia • Grade II: Moderate dysplasia • Grade III: Severe dysplasia • Some human papilloma virus (HPV) strains that cause cervical condylomas are carcinogenic and predispose to cervical neoplasia

44. Cervical Intraepithelial Neoplasia (2 of 2) • HPV genital tract infections are common • More than 80 different strains of HPV • 40 types can infect genital tract • 8 strains are high-risk types and considered carcinogenic • Common in young sexually active women • > 90% infections resolve spontaneously in 6-12 months • Some may have repeated infections • Diagnosis: HPV test to supplement Pap smear when cytologic changes in Pap smear are inconclusive (atypical squamous cells of undetermined significance) • If HPV test is negative, cytologic changes are not significant

45. Cervical epithelial dysplasia caused by papilloma virus

46. Dysplastic epithelial cell identified in Papanicolaou smear

47. Cervical Dysplasia and Carcinoma (1 of 2) • Squamocolumnar junction or transition zone • Cervical abnormalities develop first in cells at the junction between squamous epithelium at exterior of the cervix and the columnar epithelium lining cervical canal • Usually located at the external os • Pap smear shows abnormal cells • Colposcopy localizes abnormalities • Biopsies establish diagnosis

48. Cervical Dysplasia and Carcinoma (2 of 2) • Treatment depends on extent of disease • Dysplasia and in situ carcinoma • Cryocautery (freezing) • Surgical excision of abnormal area • Hysterectomy (removal of uterus) • Results are excellent • Invasive carcinoma • Radiation • Radical hysterectomy (resection of uterus, fallopian tubes, ovaries, adjacent tissues) • Results are less satisfactory

49. Endometrial Disorders • Benign endometrial hyperplasia • Associated with irregular uterine bleeding • Benign endometrial polyps • Common • May bleed if tip is eroded • Endometrial adenocarcinoma • Related to prolonged endometrial stimulation by estrogen use • Irregular uterine bleeding or postmenopausal bleeding

50. Benign endometrial hyperplasia, polypoid mass in endometrial cavity Endometrial polyp in endometrial cavity